4-(cyclopentanopolyhydrophenanthr-17-yl) imidazoles and derivatives thereof



Patented Dec. 29, 1953 4 (CYG'LOPENTANOPOLYHYDR OPHENANi- THR-l'I-YL) IMIDAZOLES AND DERIVA! 'I'IVES THEREOF Kurt Rorig, Chicago, Ill

gnor o G- D- Sea le & 00., Chicago, 111., a corporation of Illinois No Drawing. Application March 12, 21952,

Serial No. 276,238

Claims. (Cl. 260-2395) The present invention pertains to a new group of polycyclic imidazole derivatives, and more particularly, to the 4-cyclopentanopolyhydrophenanthr-17-y1imidazoles and their salts. These imidazoles can be represented by the structural formula wherein .R is a 16,17-dihydroeH-cyclopentas talpolvhyd ophenanthry nucleu attached o where n. .R. is. a 1 .1' -d y m-l5H-cyclopental l ydr phen nthre e nuc us at a d o the -CO radical through the carbon in the 17- position, and X' is a readily hydrolyzable lower acyl radical, with an aqueous solution of a lower aliphatic or aromatic aldehyde, ammonium hydroxide, and a cupric salt such as cupric acetate.

Under the influence of these reagents, there apparently occur the following three consecutive transformations (1) The radical X is hydrolyzed and replaced by a hydrogen atom.

(2) The resulting carbinol radical is oxidized to an aldehyde of the type 0 agitatin (.3). The resulting a dehyde. is. med lists! w t 2. moles, of amm nia nd .1 mo e oi as aldehyd 9! hetype .R'CHO totorm the imidazole ring; c H-NH t being a hydr g n. lewer ethyl, ower r i adical. Obviously he inte m diate r action products the abo e scheme can a o be used directly as starting materials. e the i s;

a bi l which, 2: is hvdrqten. an the afl= dicarbonyl compounds.

The. reacti a plicable to th lids-hydr ya-c t l) e 16.1 r dihvdro. 5H y onents= a1n lyhydrcphen nth e es d t e te retnendr ns, .7 s a oxyace yli der vat v s thereo Examples of suitable 17-(p-hydroxyacetyl) coup pounds are 3,2l-dihydroxy-pregnan-20-one, 3,21- dihydroxy 5 pregnen 20-one, desoxycorticosterone, corticosterone, 1l-dehydrocorticosterone, 17 hydroxydesoxyoorticosterone, 17- hydroxycorticosterone and l'Z-hydroxy-ll-dehydrocorticosterone. The 21-hydroxy group may be esterifled by such acids as formyl, acetyl, propionyl and benzoyl. Among the aldehydes suitable for this reaction are formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, benzaldehyde, p-tolualdehdye and the like. An excess over the theoretical two moles of ammonia is used to keep the cupric ion in solution.

The imidazoles which constitute this invention contain both an acidic imido group and a basic nitrogen and therefore form salts with both acids and metal ions. Among the acids which have been found useful are such inorganic and strong organic acids as sulfuric, phosphoric, hydrochloric, hydrobro'mic, sulfamic, citric, oxalic and ascorbic acids. Salts are also formed with alkali and alkaline earth metals as well as with copper, silver and, presumably, gold.

{Ifhe imidazoles which constitute this invention are valuable chemotherapeutic agents, especially because of their valuable regulatory effect on the cardiovascular system and their anti-hormonal activity. The following examples illustrate in detail certain of the imidazoles which constitute this invention and methods for their preparation. However, this invention is not to be construed as limited thereby in spirit or in scope since it will be apparent to those skilled in the art of organic synthesis that many modifications in materials and methods may be practiced without departing from the scope of this invention. In these example temperatures are given in degrees centigrade (C.) and relative amounts of materials in parts by weight.

Example 1 A solution of 4.3 parts of 36% aqueous formaldehyde, 10 parts of cupric acetate, 68 parts of 26% aqueous ammonium hydroxide and 2 parts of 3,8,21-dihydr0xy-5-pregnen-20-one 21-acetate (21-acetoxypregnenolone.) in 180 parts of absoute ethanol is re uxed o an .h r und r a niitetn atmcsphere. The soluti n, is to led to give a light gray precipitate of the copper salt of the 4-(l,2,3,4,'7,8,9,10,11,12,l3,14,16,1'7-tetradecahydro 10,13 dimethyl-35-hydroXy-15H)- cyclopenta[a]phenanthr-l'I-ylimidazole Which is collected on a filter and dried. This salt melts at about 325 C. with decomposition. A second crop of this copper salt is obtained by diluting the filtered reaction mixture with 600 parts of water.

The combined copper salts are suspended in 75 parts of water and heated on the steam bath while a stream of gaseous hydrogen sulfide is passed into the suspension for one-half hour to precipitate the copper sulfide and free the imidazole derivative. The precipitate is collected on a filter and extracted by boiling with 100 parts of absolute ethanol and hot filtration. The filtrate is concentrated to one-fifth of its original volume and cooled to yield as a precipitate the white, powdery 4 (3B hydroxy-S-androstan-l'I-yllimidazole, which melts at about 298300 C. with decomposition.

A crystalline hydrochloride is obtained by treatment of an isopropanol solution with one equivalent of a 25% solution of hydrogen chloride in anhydrous isopropanol. It has the structural formula CH-NH-HCl Example 2 A solution of 0.4 parts of isobutyraldehyde, 6 parts of cupric acetate, 50 parts of 26% aqueous ammonium hydroxide, and one part 35,2l-dihydroxy--pregnen-20-one in 90 parts of ethanol is heated at refiux temperature for 50 minutes under a nitrogen atmosphere. The mixture is then diluted with 200 parts of cold water and the grayish precipitate is collected on a filter, washed with water and dried. The copper salt of the 2-isopropyl 4. (l,2,3,4,7,8,9,10,11,l2,l3,14,l6,1'7- tetradecahydro 10,13 dimethyl 3s hydroxy- 15H) -cyclopenta[alphenanthr 1'7 ylimidazole thus obtained melts above 300 C. Treatment with hydrogen sulfide as in Example 1 yields the 2 isopropyl l-(3fi-hydroxy-5-androsten-l'l-yl) lmidazole in small, colorless, high melting crystals. It has the structural formula Example 3 A solution of 2 parts of 3 aqueous formaldehyde, 5 parts of cupric acetate. 34 parts of 26% 4 aqueous ammonium hydroxide and one part of 3,8,2l-dihydroxy-pregnan-20-one ill-acetate in 100 parts of absolute ethanol is heated at reflux temperature for an hour under nitrogen and then cooled and diluted with 200 parts of water. The brownish precipitate of the copper salt of the 4- (10,l3 dimethyl 35 hydroxyperhydro 15H) cyclopentalalphenanthr-lT-ylimidazole is collected on a filter, washed with water and dried. The salt melts unsharply above 300 C. with decomposition. The high melting, white, powdery l-(3s-hydroxyandrostan-17-yl)imidazole is iso lated as in Example 1. It has the structural formula CHNE\[ CH Example 4 A solution of 2 parts of 36% aqueous formaldehyde, 5 parts of cupric acetate, 34 parts of 26% aqueous ammonium hydroxide and one part of desoxycorticosterone acetate in 100 parts of ethanol is refluxed for an hour under a nitrogen atmosphere and then cooled. After dilution with 400 parts of water the grayish-brown precipitate is collected on a filter, washed with water and dried. There is obtained the copper salt of 4 (1,2,3,6,'7,8,9,l0,l1,l2,13,14,16,17 tetradecahydro-10,l3-dimethyl-3-oxo 15H) cyclopentalal phenanthr-l'I-ylimidazole which decomposes at a temperature above 300 C. The free imidazole is liberated by treatment with hydrogen sulfide as in Example 1. This 4-(3-oxo-4-androsten-1'1- CHI-NH Example 5 A solution of 20 parts of desoxyoorticosterone, 100 parts of cupric acetate, 15.5 parts of acetaldehyde and parts of 26% ammonium hydroxide in 800 parts of ethanol is heated to boiling in a nitrogen atmosphere. Then 36 parts of additional 26% ammonium hydroxide and 15.5 parts of acetaldehyde in 400 parts of ethanol are added and heating at reflux temperature in a nitrogen atmosphere is continued for 55 minutes. At that time an additional quantity of 23 parts of 26% ammonium hydroxide is added and after 30 minutes of further heating at reflux temperature the mixture is diluted with 800 parts of water and cooled in an ice bath. The brownish copper salt of the 2-methy1-4-(l,2,3,6,7,8,9,10,11,12,

13;;1e; 1-e; 1*.-'z s tetradecahydroe- 11mm s lameness,- oxo 15H) cyclopenta[alphenanthr-l'l-ylimidazole is collected on a filter, suspended in 500 parts of hot Water and :treated with a stream of hydrogen sulfide for 30 minutes, After cooling and filtration the black residue i s extracted with 600 parts of ethanol and the yellow extract is concentrat d to a .isvrua T the latter treated with 50 parts or acetone to induce crystallization of the "2-methyl-4-(3-oxo-4-androsten-17- yDimidazole which melts at about 241-244 Q. w th zdecomh sit en, the stenetur formula Example 6 A mixture of '7 parts of benzaldehyde and 50 parts of cupric acetate in 400 parts of 26% aqueous ammonium hydroxide with 10 parts of desoxycorticosterone acetate in 1200 parts of ethanol is heated at reflux temperature for 90 minutes under a nitrogen atmosphere. The mixture is cooled and diluted with 2000 parts of water whereupon the brown precipitate of 'the copper salt of the 2-phenyl-4-(1,2,3,6,7,8,9,10,11, 12,13,14,16,17 tetradecahydro 10,13-dimethyl- 3 oxo H) cyclopentaEalphenanthr 17-yl) imidazole is collected on a filter and washed with water. This copper salt melts unsharply above 300 C. The free imidazole is isolated as in Example 1 as a high melting, whitish, microcrystalline powder. This 2-phenyl-4-(3-oxo-4-androsten-17-yl)imidazole has the structural formula OH-NH Example 7 A solution of 10 parts of 36% aqueous formaldehyde, 25 parts of cupric acetate, 170 parts of 26% aqueous ammonium hydroxide, and 5.2

parts of 17-hydroxydesoxycorticosterone 21-ace-,

tate in 450 parts of absolute ethanol is refluxed for 90 minutes under nitrogen and then cooled to yield the grayish-brown precipitate of the copper salt of 4-(1,2,3,6,7,8,9,10,11,12,13,'l4,16,17- tetradecahydro 10,13 dimethyl 3 oxo l7- hydroxy 15H) cyclopentalalphenanthr 17- ylimidazole which melts unsharply above 280 C. The free imidazole is liberated as in Example 1 and obtained in the form of small, white, crystalline needles. This 4 (3 oxo 17 hydroxyformula V q Example ,8

A solution of 0.6 part of propionaldehyde, l0 he itate, 1 0 parts toil-26% aqueous ammonium hydroxide and 2 parts of 17- hydroxycorticosterone acetate in 200 parts of ethanol is heated at reflux temperature for minutes under a nitrogen atmosphere. After cooling the brownish precipitate of the copper salt is collected on a filter, washed with water and dried. It decomposes above 300 C. An

additional yield is obtained by diluting the filtrate with a large volume of water. Treatment with hydrogen sulfide, as in Example 1, yields the free 2 ethyl 4 (3 oxo 11,17 dihydroxy wherein R is a member of the class consisting of 17-androstane and 1'7-androstene radicals containing a member of the class consisting of oxo and hydroxy radicals in at least one of the positions 3, 11 and 17 and wherein R. is a member of the class consisting of hydrogen, lower alkyl and phenyl radicals.

2. 4-(3p-hydroxy-5-androsten-17-yl)imidazole. 3. A compound of the structural formula GHNH ll C---N/ wherein R is a 3-hydroxyandrosten-l7-yl radical.

4. 4-(3oxo-4-androsten-17-yl)imidazole. 5. A compound of the structural formula wherein R is a 3-oxoandrosten-17-y1 radical.

6. 4-(3p-hydroxy-androstan-1'7-yl)imldazole. 10. A compound of the structural formula 7. A compound. of the structural formula err-N11 CH-NH 0 (lower alkyl) OH 5 C---. I l R wherein R is a S-hydroxyandrostan-l'Y-yl radiwherein R is a, 3-oxoandrosten-17-y r al. KURT RORIG.

8. 2 methyl 4 (3 0x0 4 androsten 1'7- 10 yl) imidazole. I

A compound of the structural formula References Crted 1n the file of thl. patent CH-Ng UNITED STATES PATENTS u Y 5 Number Name Date 2,161,298 Miescher June 13, 1939 wherein R is a 3-hydroxyandrosten-1'7-yl radical. 

1. A COMPOUND OF THE STRUCTURAL FORMULA 